Long-term metformin therapy and vitamin B12 deficiency: An association to bear in mind

Table 2 Proposed criteria for cost-effective screening and subsequent intermittent periodic testing of vitamin B12 status in metformin-treated patients

Proposed criteria
(1) A comprehensive assessment of vitamin B12 status aimed to accurately detect a true tissue vitamin B12 deficiency should include at least one biomarker of circulating vitamin B12 (total vitamin B12 or HoloTC) coupled with one functional (metabolic) biomarker of vitamin B12 status (MMA and/or total homocysteine). A recent complete blood count is also recommended
(2) Screening for vitamin B12 deficiency should be performed in the presence of one or more of the following risk factors or conditions: (a) Strong clinical suspicion of deficiency: clinical evidence of vitamin B12 deficiency, including unexplained macrocytic anemia, neurological symptoms and peripheral neuropathy1; (b) Preexisting diabetic peripheral and/or autonomic neuropathy2; (c) Duration of metformin treatment ≥ 5 yr; (d) Older adults: age ≥ 65 yr; (e) High cumulative metformin exposure defined by a MUI value of > 5 (this criterion applies to patients with type 2 diabetes treated with metformin for at least 6 mo)3; (f) Metformin dose of ≥ 1500 mg/d for a duration of at least 6 mo (the highest risk of vitamin B12 deficiency has been observed with a daily metformin dose of ≥ 2000 mg); (g) Concomitant long-term use (≥ 12 mo) of acid-suppressing medications such as PPIs and H2RAs; and (h) Concomitant presence of risk factors or comorbidities associated with an increased risk of vitamin B12 deficiency (reviewed in Table 1) warrants screening for deficiency based on clinical judgement

¹Based on results from Diabetes Prevention Program/Diabetes Prevention Program Outcomes Study[32], peripheral neuropathy refers to monofilament-defined neuropathy (detection of an abnormal monofilament examination).

²Screening for vitamin B12 deficiency should be routinely performed in metformin-treated diabetic patients with a preexisting diabetic peripheral and/or autonomic neuropathy. Once diagnosed, metformin-induced vitamin B12 deficiency should be corrected promptly in such patients in order to counteract the exacerbation of nerve damage and prevent the development or progression of a mixed “diabetic and metformin-induced cobalamin deficiency-related neuropathy”.

³Metformin Usage Index (MUI) is defined as the product of the daily metformin dose (mg) and its duration (yr) divided by 1000. For example, 1000 mg of metformin used for a duration of 1 yr is equivalent to 1 MUI (1000 × 1/1000 = 1 MUI). This criterion applies to patients with type 2 diabetes treated with metformin for at least 6 mo, based on the results from the prospective observational study conducted by Shivaprasad et al[45]. H2RAs: Histamine H2-receptor antagonists; HoloTC: Holotranscobalamin; MMA: Methylmalonic acid; MUI: Metformin Usage Index; PPIs: Proton-pump inhibitors.